Experiments are proposed to characterize the effects of long-term opiate administration on adrenergic receptor function in the mammalian brain. Receptor binding techniques will be used to evaluate changes in the number and/or affinity of alpha- and beta-type adrenergic receptors in somatosensory cortex, cerebellum and hippocampus of rat following prolonged administration of morphine. The aim will be to correlate biochemical measures of shifts in alpha1, alpha2 and beta adrenoceptors in these structures with electrophysiologically demonstrable changes in sensitivity of relevant postsynaptic target neurons to noradrenergically mediated effects. Changes in neuronal responsiveness to noradrenergic action will be assessed in vivo and in the in vitro hippocampal slice using extracellular and intracellular recording techniques in combination with microiontophoresis and bath perfusion of drugs. These studies will enable us to determine whether chronic administration of morphine leads to supersensitivity of postsynaptic adrenoceptors. Presuming this to be the case, the relationship of adrenergic receptor supersensitivity to the phenomena of opiate tolerance and dependence will then be examined in similar tests performed on animals treated chronically with UM 1071, a benzomorphan derivative which has selective affinity for the kappa opiate receptor. To explore this issue further, attempts will also be made to temporally correlate changes in adrenergic ligand binding and adrenoceptor response with the onset of tolerance to morphine action and the occurrence of selected signs of precipiated withdrawal. Overall, the proposed research will contribute to a basic understanding of the involvement of central noradrenergic mechanisms in the mediation of the physiological and behavioral changes associated with chronic opiate abuse.